The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has reported that about one quarter of the US adult population suffers from obesity and over half of the population is overweight (see, e.g., www.niddk.nih.gov/health/nutrit/pubs/statobes). Furthermore, the yearly statistics show that the prevalence of obese and overweight people is trending upward. This has resulted in an increase in health-related costs due to the greater incidence of such related diseases as heart disease and diabetes. In 1998, it was reported that the direct economic cost of obesity in the US was $56 billion, a number comparable to the health cost of cigarette smoking. Wolf and Colditz, Obes. Res. 1998; 6(2):97-106. For health reasons and overall well-being, a safe and effective treatment for overweight conditions would be highly desirable. Accordingly, there has long been scientific interest in understanding biochemical mechanisms that might provide insight into this problem.
The MCH receptor (melanin concentrating hormone receptor, MCH1 MCH-R, or MCH-R1) is a receptor that has been implicated in the regulation of body weight. It is a 353 amino acid protein that is a member of the Class 1 rhodopsin-like G-protein coupled receptor (GPCR) subfamily. The receptor is found throughout the central nervous system and is predominantly expressed in the hypothalamus and zona incerta. To a lesser extent, the receptor is also found in various peripheral tissues such as in the skeletal muscle, eye, tongue, pituitary, testes, stomach and intestines. Mice deficient in MCH-R1 are lean, hyperactive, have altered metabolism and neuroendocrine profiles, and are less susceptible to diet induced obesity (Marsh, D J, et al., Proc. Natl. Acad. Sci., 99: 3240-3245 [2002]).
An endogenous ligand of MCH-R1 is MCH. Mammalian MCH is a highly conserved 19 amino acid cyclic peptide which is reportedly involved in processes related to feeding, water balance, energy metabolism, general arousal and attention state, memory and cognitive functions, and psychiatric disorders (see e.g., International publication no. WO 00/39279 and references cited therein).
A role for MCH in the central control of feeding and the regulation of body weight has been suggested by the observations that fasting increased MCH mRNA in both obese and normal mice. MCH also stimulated feeding in normal rats when injected into the lateral ventricles, and MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice (Herve and Fellman, 1997; Rossi et al., 1997; Qu et al., Nature, 380:243-247 [1996]). Furthermore, following insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres were observed concurrent with a significant increase in the level of MCH mRNA. Treatment of rats with leptin resulted in decreased MCH mRNA levels in the hypothalamus along with decreased food intake and body weight gains (Bahjaoui-Bouhaddi et al., 1994; Sahu, 1998).
The MCH-R1 receptor is also reported to play a role in the regulation of sexual activity, stress-related disorders, Parkinson's disease, Huntington's Chorea, neurodegenerative disorders, mental illness such as schizophrenia, depression, epilepsy and memory retention.
Together the above-described data show a role for endogenous MCH and its cognate receptor MCH-R1 in the regulation of energy balance and response to stress. Accordingly, there is a strong rationale to develop new compounds that modulate MCH-R1 activity. It would be useful to provide small molecules that are effective as antagonists of MCH-R1 in order to treat metabolic disorders such as obesity, stress-related disorders, and the aforementioned diseases associated with MCH-R1 activity.